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Night Before or After Pill To Prevent HIV Transmission
  "A phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1 transmission in uninfected subjects at high risk"
The study authors are conducting this preliminary study to see if there is evidence that brieg periodic low dose nevirapine could prevent HIV transmission as a prevention tool. Background was offered by study investigators on why to study this. At present there is no vaccine that has proven to be effective in preventing sexual or blood-borne HIV-1 transmission. The HIVNET 012 randomized controlled trial was able to show that a single dose of nevirapine safely and effectively reduced mother-to-infant HIV-1 transmission by 47% at 14-16 weeks of age when given in labor to the mother and to the infant within 3 days of birth. Therefore, a low-dose regimen of nevirapine may be effective and safe in preventing HIV-1 sexual or blood-borne transmission in adults practicing high-risk behaviors. The use of a low-dose regimen of nevirapine for pre-exposure prophylaxis of an individual is particularly attractive if targeted to seronegative high-risk individuals, such as commercial sex workers, injection drug users, men who have sex with men, and seronegative individuals with HIV-infected sex partners (i.e., discordant couples). The use of such a regimen during periods of high-risk exposure may be effective and feasible, much like the weekly use of mefloquine for malaria prophylaxis. This type of intervention may be cost effective for individuals at very high risk for limited periods of time and could be used as part of a substance abuse rehabilitation program, during the first several months of an HIV-1 vaccine regimen, during periods of commercial sexual activity, or during periods of sexual activity with known HIV-1-positive sexual partners. Such a potentially toxic intervention would also be ethical especially in populations in which behavioral interventions have had limited success and HIV-1 seroincidence is high. The cost of a 6-month course of nevirapine taken once a week would be approximately $10 using the publicly stated 90% price discount for developing countries.
Nevirapine is a licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for use in the treatment of HIV-1 infection (when used in combination with other antiretroviral drugs) and for the prevention of HIV-1 perinatal transmission in some developing countries. Nevirapine has a number of desirable characteristics, such as rapid absorption, a long half-life, excellent tissue penetration, low plasma protein binding (60%), rapid and potent antiretroviral activity, activity against intracellular and extracellular virus, and minimal side effects at low doses. The concentration to give 50% inhibition (IC50) for nevirapine is approximately 10 ng/ml, which is approximately 400-500 times lower than the steady-state plasma concentrations achieved with treatment dosing regimens of 400 mg per day. The half-life of nevirapine is approximately 25-30 h with a daily 400 mg oral dose and 60 h after a single 200 mg dose. The pharmacokinetics of chronic low-dose nevirapine regimens are not known, nor is the plasma nevirapine concentration needed to prevent HIV-1 transmission, which may be different for prevention of perinatal, sexual, and blood-borne transmission.
This phase I/II three-arm dose escalation trial (HIVHOP 101) was carried out to evaluate the safety, tolerability, and nevirapine trough levels when HIV-1-uninfected participants at high risk for HIV-1 infection were given 200 mg nevirapine once weekly, twice weekly, or every other day for 12 weeks. Although the blood concentration level of nevirapine needed to protect against HIV-1 infection is not known, dosing regimens were chosen that could potentially keep the trough level of nevirapine above 100 ng/ml, which is 10 times the IC50.
This study is a phase I/II trial (HIVHOP 101) in which 33 such uninfected subjects received a 200 mg tablet of nevirapine once weekly (cohort A, n = 12), twice weekly (cohort B, n = 12), or every other day (cohort C, n = 9) for 12 weeks. Clinical signs/symptoms, laboratory parameters, and nevirapine trough levels were assessed at entry and at 1, 2, 4, 6, 9, and 12 weeks, with a follow-up sample at 16 weeks.
Participants were men and women recruited through advertisements placed on the Johns Hopkins Medical campus, in local community newspapers, and by the HIV clinical trials outreach team. Interested subjects were seen by trained counselors in the Moore Clinic at the Johns Hopkins Hospital. Following pretest counseling and consented screening for HIV-1 infection, subjects were eligible for the study if they were aged 18 years or older, were HIV-1 antibody negative, and were injection drug users, sex partners of injection drug users, a man who has sex with other men, sex partners of known HIV-1-infected individuals, and/or individuals with unprotected sexual exposures with multiple partners within the past 12 months.
Subjects were specifically counseled about how to minimize their risk for HIV-1 infection and told that they should not engage in high-risk behavior in the belief that nevirapine might be protective. Subjects were also specifically informed that if they became infected with HIV-1 during the study while taking nevirapine their treatment options with nevirapine and other NNRTI might be limited because of the possibility of nevirapine resistance engendered as a result of their participation in the study.
Subjects in cohorts A, B, and C orally self-administered a 200 mg tablet of nevirapine once weekly, twice weekly, or every other day for 12 weeks, respectively. The nevirapine tablets were provided in sufficient quantity in blister packs labeled with the study dose. Subjects stopped taking nevirapine if the ALT, AST, or GGT values increased to > 5 times ULN and > 4 times their baseline value at entry. If on stopping study drug, liver enzymes returned to baseline levels, dosing of nevirapine was restarted, and the regimen was completed if tolerated. Study visits were scheduled so that subjects were able to take their next dose of nevirapine during the study visit, allowing a nevirapine trough level to be obtained and allowing administration of study drug to be directly observed during those study visits.
No subject experienced clinical symptoms attributed to nevirapine, including rash. There were no significant changes in liver enzyme levels from baseline to week 12 in the three cohorts, except for glutamyl transpeptidase in cohort B. Median nevirapine trough levels at weeks 1 and 12 were 119 ng/ml (range, < 25-205) and 135 ng/ml (range, < 25-1065), respectively, for cohort A, 569 ng/ml (range, 135-2641) and 431 ng/ml (range, 42-2454) for cohort B, and 1942 ng/ml (range, 1214-2482) and 943 ng/ml (range, 262-5281) for cohort C. No subject became HIV-1 antibody positive by week 16.
The nevirapine trough levels (median ng/ml [range] in cohort A at week 1 was 119 (range <25-205), at week 12 it was 135 (<25-1065); in cohort B at week 1 trough was 569, and at week 12 431; incohort C at week 1 trough levels were 1942, and 943 at week 12. Nevirapine IC50=10 ng/ml. Average steadt state trough nevirapine concentration at 400 mg/day is 45001900 ng/ml. The lower limit of detection of nevirapine assay is 25 ng/ml. As shown below some study subjects had <25 ng/ml nevirapine trough levels in blood, but only in the cohort A dose regimen, which was 200 mg once weekly. In cohorts B and C where dosing was twice weekly or every other day no one had <25 ng/ml, and perhaps more importantly only 3 study subjects had <100 ng/ml trough levels.
In cohort A, nevirapine levels > 25 ng/ml were detected in trough level samples of 7 of 11 participants at all six time points through weeks 1 to 12 (range, 85-385), in 2 of 11 participants at five of six time points (range, < 25-315), and in 2 of 11 participants at two of six time points (range, < 25-1065). In cohort B, nevirapine levels > 25 ng/ml were detected in seven of eight participants at all six time points through weeks 1 to 12 (range, 26-2708) and in one subject at five of six time points. In cohort C, nevirapine levels > 25 ng/ml were detected in all five participants at each time point tested through weeks 1 to 12 (range, 31-9261). There was no significant difference in trough level between weeks 1 and 12 in cohorts A, B, and C, but the median level at 12 weeks was approximately half that seen at week 1 in cohort C. Three subjects in cohort B attained nevirapine trough levels between 2000 and 3700 ng/ml at several time points. Three of five subjects in cohort C attained nevirapine trough levels > 2500 ng/ml at several time points, with one subject having a level of 9261 ng/ml. However, three subjects in cohort B and two subjects in cohort C had nevirapine trough levels that varied by more than fivefold, which could not be explained by different dosing intervals and suggested poor adherence and/or variable dosing in some subjects.
In cohort C, there was no statistically significant increase in liver enzyme values from entry to week 12. However, one subject, who was HCV antibody positive, experienced an increase in AST, ALT, and GGT values from 31 to 67 IU/l, 32 to 144 IU/l, and 17 to 123 IU/l, respectively, from entry to week 12.
Of the six HCV antibody-positive subjects followed after entry into the study, liver enzyme values generally increased, with two subjects having an increase of at least one liver enzyme value during the study that was >5 times ULN and >4 times the level at entry.
In terms of clinical adverse events, 8 of 12 enrolled subjects in cohort A, 5 of 12 in cohort B, and 5 of 9 in cohort C experienced at least one clinical adverse event. The adverse events were variable in nature among the three cohorts and did not appear to increase with dose (nausea, headache, infection, respiratory, vomiting, gastrointestinal, fever). No subject in any of the cohorts experienced clinical signs or symptoms attributed to the study drug, including rash. Of the 30 clinical adverse events after entry into the study, 25 were graded as mild and five as moderate. None were considered severe or life threatening.
The authors concluded a single dose of nevirapine taken once weekly, twice weekly, or every other day for 12 weeks was safely tolerated by the subjects in this small study, and resulted in nevirapine levels well above the IC50 (inhibitory concentration of 50%: 10 ng/ml) over the 12-week period in nearly all evaluable subjects. These data suggest that a single 200 mg dose of nevirapine taken once weekly, twice weekly, or every other day for 12 weeks was well tolerated, resulted in minimal or no hematologic or liver toxicity, and achieved nevirapine trough plasma levels > 100 ng/ml in most subjects.
The overall reported incidence of nevirapine-related serious adverse events in adults who received nevirapine monotherapy for treatment is 3.3%, with rash being the most commonly observed serious adverse event, occurring in 1.4% of patients. The Centers for Disease Control and Prevention (CDC) have not included nevirapine on the expanded list of antiretroviral drugs recommended for post-exposure prophylaxis because of reported serious life-threatening liver toxicity and rash with the use of nevirapine for post-exposure prophylaxis in HIV-1-uninfected individuals. However, the doses of nevirapine used in those instances were 2 to 14 times the dosing used in this protocol. Moreover, at least 21 of 22 subjects who experienced serious toxicities with post-exposure prophylaxis in this CDC report were also taking at least two other potentially toxic antiretroviral drugs in addition to nevirapine. In our study, three subjects had an increase in one or more liver enzymes > 5 times ULN and >4 times the level at entry, but in at least two of these subjects the increases were thought to be unlikely related to nevirapine. However, subjects with elevated liver enzymes > 3 times ULN were excluded from the study, so toxicity may have been greater had they been enrolled. Likewise, 9 of 33 enrolled subjects dropped out of the study before completion of the 12-week regimen, so adverse events among these subjects cannot be excluded. The percentage of subjects who dropped out of the study did increase with increasing dose, suggesting a possible toxicity problem. However, in this dose escalation trial, the increasing dosing frequency may have been a deterrent to staying in the study. The increasing loss to follow-up rates in each cohort with increasing dose could also have reflected the differences in the subject population in each cohort. For example, gay white males constituted 8 of 12 subjects in cohort A, 2 of 12 in cohort B, and none of 9 in cohort C.
Seven of the subjects in this study were infected with HCV, of whom six were followed after entry. Two of these subjects showed a modest increase in liver enzymes, and a third had > 5 times ULN and > 4 times the level at entry for AST and ALT, which was thought to be a consequence of heavy alcohol ingestion. These data suggest that low-dose nevirapine should be used cautiously in HCV-infected subjects, especially if taken chronically. The one subject with chronic HBV infection became HBsAg negative within 2 weeks of starting a once weekly dose of nevirapine. This observation deserves further study in additional subjects.
In our study, there appeared to be no decrease in nevirapine trough levels from week 1 to week 12 at either once weekly or twice weekly dosing, but the trough levels at week 12 were approximately half those at study entry in cohort C, taking the drug every other day. These results are consistent with the observation that nevirapine is an inducer of hepatic cytochrome P450 metabolic enzymes such that autoinduction by nevirapine results in a corresponding decrease in its terminal phase half-life in plasma from approximately 45 h (single dose) to approximately 25-30 h following multiple dosing with 200-400 mg/day. The autoinduction of nevirapine metabolism appears to be concentration related given the absence of this phenomenon at the lower concentrations associated with the less-frequent dosing intervals. The vast majority of nevirapine-associated rash and hepatitis toxicity occurs during the first 6 weeks of chronic nevirapine administration and may be immune related; consequently, it is unlikely that toxicities will increase with prolonged use. However, long-term safety in this population needs to be assessed.
The fact that several participants in cohorts B and C had nevirapine trough levels frequently > 2000 ng/ml, and in one case > 9000 ng/ml, is worrisome, as the steady-state nevirapine trough levels attained at 400 mg/day is 4500 1900 ng/ml, a level at which rash and/or liver toxicity may occur. Given the variability of trough levels in some subjects in our study, these high levels may be caused by erratic self-administration of nevirapine. It should be noted that a 200 mg dose of nevirapine every other day is one-fourth the recommended treatment dose. The data suggest that even with weekly dosing the trough level is > 10 times the IC50 of nevirapine in the majority of participants and should be well above the IC50 nearly all the time if doses are taken as directed. However, because the level of regimen needed to prevent blood-borne or sexual HIV-1 transmission is unknown, a more frequent dosing schedule may be more effective. In addition, isolates from HIV-1-infected subjects taking nevirapine monotherapy develop reduced susceptibility to nevirapine (> 100-fold IC50 or > 1000 ng/ml) by 8 weeks from time of initiation of drug. Therefore, at least every other day dosing might be required to keep trough levels of nevirapine high enough to protect against transmission of resistant virus.
A potential drawback to the use of nevirapine or any NNRTI as a protective measure is that high-level resistance will emerge quickly should a subject have or acquire HIV-1 infection while taking a monotherapy regimen, which will potentially limit treatment options with NNRTI. However, if such a pre-exposure prophylactic regimen is effective in preventing HIV-1 transmission, then the risk of resistance would seem acceptable from a public health perspective. Other recently licensed drugs such as tenofovir, which has less cross-resistance, less potential toxicity, and a long half-life, would also be good candidates for this type of intervention.
Given the sustained plasma nevirapine levels reported in this study, a larger safety trial is warranted, which may be designed to collect preliminary information regarding efficacy using one or more of these low-dose nevirapine regimens.
AIDS 2003;17:547-553
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